19-hydroxyaldosterone and its preparation

ABSTRACT

There is provided the novel compound 19-hydroxyaldosterone. There is provided a process for its preparation. There are further provided pharmaceutical compositions comprising this compound as active ingredient. These are useful, amongst others, as mineralocorticoid drugs and as drug against Addison&#39;s disease.

FIELD OF THE INVENTION

A novel steroid compound, 19-hydroxyaldosterone has been prepared. Thiscompound exhibits full mineralocorticosteroid activity in the Kagawabioassay.

The invention relates to functional derivatives of the above compoundand a process for the preparation thereof.

It also relates to pharmaceutical compositions containing such compoundsas active ingredients. The compounds are of value, amongst others, inthe treatment of Addison's disease.

BACKGROUND OF THE INVENTION

Steroids, such as 11-deoxycorticosterone and androstenedione, having anhydroxy substituent at the 19-position, have been described recently andhave been shown to be of interest. 19-Hydroxy-11-deoxycorticosterone wasdetected in regenerating rat adrenal incubations, and it was alsodetected as a product of 11-deoxycorticosterone metabolism by ratadrenal. It was further discovered that 19-hydroxyandrostenedione is apotent hypertensinogenic steroid in humans.

SUMMARY OF THE INVENTION

The invention relates to the novel compound 19-hydroxyaldosterone and tofunctional derivatives thereof. It further relates to a process for theproduction of these compounds.

It further relates to pharmaceutical compositions containing same asactive ingredient.

The novel compounds are of value in human medicine. They exhibitmineralocorticoid activity causing sodium retention and raising bloodpressure. The compounds of the invention are of value in the treatmentof Addison's disease. They are also of value in the study of theetiology of hypertension. Preliminary studies indicate that the compound19-hydroxyaldosterone causes anti-natriuresis and kaliuresis at a doseof about 25 micrograms per rat. In short-circuit current measurements itwas shown that the compounds showed mineralocorticoid activityapproaching that of aldosterone. The compound exists as a mixture ofmainly two isomers, and the invention relates to the isomeric mixture aswell as to each of the individual isomers.

The pharmaceutical compositions of the invention comprise the activeingredients in combination with a suitable conventional adjuvant orcarrier. The 19-hydroxyaldosterone was prepared by a sequence of processsteps as set out in the enclosed reaction schemes. It is clear that thisreaction scheme can be modified at will.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel compound 19-hydroxyaldosterone is prepared, in accordance withthe present invention, by the process illustrated in the accompanyingdrawings, in which:

FIG. 1 is a flow sheet illustrating the conversion of the raw material,21-acetoxy-5-pregnene-3,20-dione-di-(ethylene ketal)-18,11β-lactone (1),to the intermediate 3β,21-dihydroxy-5-pregnen-20-one-20-ethyleneketal-18,11β-lactone (4a), or the 3,21-diacetate (4b) thereof; and

FIG. 2 is a flow sheet showing the conversion of the diacetate to thedesired 19-hydroxyaldosterone product 12(a,b).

Thus, according to a preferred embodiment of the invention the reactioncomprises the following steps:

The starting material was 21-acetoxy-4-pregnene-3,20-dione-20-ethyleneketal-18,11β-lactone in which the double bond was moved from the 4,5- tothe 5,6-position by enol acetylation to3,21-diacetoxy-3,5-pregnadien-20-one-20-ethylene ketal-18,11β-lactone,followed by borohydride reduction and acetylation by conventional means,giving 3,21-diacetoxy-5-pregnen-20-one-20-ethylene ketal-18,11β-lactonewhich was converted to the corresponding 6β,19-oxido compound byaddition of hypobromous acid followed by the hypoiodite reaction of thebromohydrin, followed by mild saponification to yield the correspondingdiol, 5-bromo-6β,19-epoxy-3β,21-dihydroxy-5α-pregnan-20-one-20-ethyleneketal-18,11β-lactone, followed by selective oxidation to thecorresponding 3-one, which was dehydrobromiated to6β,19-epoxy-21-hydroxy-4-pregnene-3,20-dione-20ethyleneketal-18,11β-lactone, subjecting same to reductive ring opening toprovide a mixture of 19,21-dihydroxy-4-pregnene-3,20-dione-20-ethyleneketal-18,11β-lactone and the corresponding 5-ene isomer, converting theabove mixture to the 3,20-diketal and subjecting same to reduction withdiisobutyl aluminum hydride to the hemiacetal11β,18-epoxy-18,19,21-trihydroxy-5-pregnene-3,20-dione-3,20-di-(ethyleneketal), which was hydrolyzed to the desired 19-hydroxyaldosterone.

This compound can be easily converted by conventional processes to avariety of 18,19- and 21-mono, di- and triesters in the formula ##STR1##and 19- and 21-mono and diesters in the isomeric compound of formula##STR2##

EXPERIMENTAL

Merck A.G. silica gel ("60", mesh 70-230) was used in columnchromatography. TLC was performed with acetone-hexane or CHCl₃ -ethanolmixtures and the plates (silica gel Merck F254) were sprayed with 10% H₂SO₄ in ethanol before heating. ¹ H-NMR spectra (in CDCl₃ with TMS asinternal standard) were obtained with a Bruker WH-90 or AM-360spectrometer equipped with an ASPECT 3000 computer. Ppm values obtainedon the latter instrument are reported with three digits after thedecimal point, I.r. spectra were recorded with a Perkin-Elmer 297spectrometer. Mass spectra were recorded with a Finnigan 4021spectrometer:ionizing conditions for EI 17-19 EV, for CI (isobutane) 70EV; source temperature 260° C., inlet temperature 200°-250° C. Meltingpoints were determined in capillaries with the Electrothermal apparatusand are uncorrected. The following abbreviations are used in the text:dichloromethane, MDC; ethyl acetate, EtOAc.

21-Acetoxy-4-pregnene-3,20-dione-20-ethylene ketal-18,11β-lactone (2)

A solution of 19.3 g of 21-acetoxy-5-pregnene-3,20-dione-di-(ethyleneketal)-18,11β-lactone (1) in 300 ml of dioxane was treated with 7 ml of0.5N HCl and allowed to stand at 20° C. for 3 days with occasional TLCmonitoring (acetone-hexane 1:2). Addition of 500 ml of water and 100 mlof saturated aq. NaHCO₃ was followed by three extractions with MDC,drying of the extracts with Na₂ SO₄ and evaporation in vacuo at 40° C.The gum was chromatographed on 800 g of silica gel using PE-acetone 4:1containing a trace of Et₃ N, collecting 250 ml fractions. Flasks 25-38gave 3.8 g of starting diketal 1, while fractions 54-84 furnished 10.6 gof the desired 3-one 2, m.p. 155°-160° C. (reported 160°-2° C.). Elutionwith a 1:1 solvent mixture yielded varying amounts of21-hydroxy-4-pregnene-3,20-dione-18,11β-lactone.

3,21-Diacetoxy-3,5-pregnadien-20-one-20-ethylene ketal-18,11β-lactone(3) and 3β,21-dihydroxy-5-pregnen-20-one-20-ethyleneketal-18,11β-lactone (4a)

An ice-cold solution of 4.3 g of 2 in 50 ml of acetic anhydride wastreated with 5 ml of trimethylchlorosilane followed by 7.5 g of NaI(weighed out under N₂) and swirled with occasional ice-cooling, withprecipitation of NaCl. The mixture was kept in the dark at roomtemperature for 1 h, then poured in a thin stream into a mechanicallystirred suspension of 250 g of ice in 150 ml of aq. saturated NaHCO₃solution and 200 ml of MDC. Ten ml of 5% sodium bisulfite solution wasadded, the aqueous phase was reextracted with 2×150 ml portions of MDC,and the combined extracts were treated with 1 ml of pyridine and driedwith Na₂ SO₄. The solvents were removed in vacuo, finally with the aidof an oil pump at 55° C. (bath temperature). The residual oil wastreated with 2 drops of pyridine and 20 g of ice to decompose anyresidual acetic anhydride and initiate crystallization of the enolacetate 3, exhibiting λ^(KBr) _(max) 5.66 and 5.74 (sh) μ. It was washedwith water by decantation, directly treated with 130 ml of ethanol and6.7 g of sodium borohydride, and the suspension was refluxed for 30 min.Most of ethanol was then removed on the steam bath with a stream of N₂and 200 ml of water was added. The clear solution was heated for anadditional 30 min, cooled in ice, poured into a 1 L separatory funnelcontaining 400 ml of MDC, acidified with 15 ml of acetic acid, and thelactone was extracted with a total of 700 ml of MDC. The combinedextracts were washed with aq. NaHCO₃, dried with Na₂ SO₄ and evaporatedin vacuo. The residue was treated with a little ether, the diol 4acollected and washed with ether: 3.37 g, m.p. 206°-212° C. The puresample had m.p. 214°-6° C. (acetone with a trace of Et₃ N); λ^(KBr)_(max) 2.96 and 5.66μ; δ 1.123 (s, 19-CH₃), 2.93 (dd, J=11.6, 12-H),3.41 (m, 3α-H), 3.46, 3.54 (ABq, J=7, 21-H₂), 3.98 (m, 20-dioxolane),4.73 (d, J=6, 11α-H) and 5.28 (brd, J=3.5, 6-H) ppm; EI: m/z 386 (M⁺--H₂ O; 5%), 374 (M⁺ --CHOH; 100)(usual fragmentation in21-ol-20-dioxolanes), 356 (M⁺ --OHOH--H₂ O; 16), 312 (M⁺ --CHOH--CO₂ ;9) and ##STR3##

The 3,21-diacetate 4b, prepared in the usual manner with aceticanhydride and pyridine, had m.p. 161°-4° C. (ether-PE); λ^(KBr) _(max)5.68 and 5.76μ; δ 1.136 (s, 19-CH₃), 2.034, 2.082 (s,s, 3-OAc, 21-OAc),2.98 (dd, J=11;6, 12-H), 3.97 (m, 20-dioxolane), 3.97, 4.08 (d,d, ABq,J=12, 21-H₂), 4.59 (m, 3α-H), 4.74 (d, J=6, 11α-H) and 5.39 (brd, J=3.5,6-H) ppm; EI: m/z 416 (M⁺ --HCOAc; 100%), 356 (M⁺ --CHOAc--AcOH; 93),312 (M⁺ --CHOAc--AcOH--CO₂ ; 16) and ##STR4##

3β,21-Diacetoxy-B 5-bromo-6β-hydroxy-5α-pregnan-20-one-20-ethyleneketal-18,11β-lactone (5)

An ice-cooled solution of 3.0 g of 4b in 60 ml of dioxane was treatedwith 7.6 ml of 4.6% aq. perchloric acid, followed in portions over a 5min period by 3.3 g of N-bromoacetamide. After 30 min at roomtemperature in the dark the solution was shaken with a mixture of 150 mlof saturated aq. NaHCO₃, 100 ml of water, 40 ml of 5% aq. sodiummetabisulfite solution and 200 ml of MDC, and then reextracted with 2×50ml portions of MDC. The combined extracts were dried with Na₂ SO₄ andevaporated in vacuo to an oil containing 5, which was best directlyconverted to 6b without further purification. A 100 mg sample waschromatographed on 10 g of silica gel: elution with PE-acetone 4:1 gaveat first a trace of the starting 4b followed by the bromohydrin 5, 41mg, m.p. 156°-160° C. (dec.) The pure sample had m.p. 166°-167° C.(methanol); λ^(KBr) _(max) 2.91, 5.65, 5.72 and 5.85μ; δ 1.415 (s,19-CH₃), 2.033, 2.079 (s,s, 3-OAc, 21-OAc), 2.921 (dd, J=11.3;6.3,12-H), 3.99 (m, 20-dioxolane), 3.99 (m, 21-H), 4.093 (d, J=11.8, 21-H),4.188 (brs, 6α-H), 4.67 (d, J=6.2, 11α-H) and 5.45 (m, 3α-H) ppm.

3β,21-Diacetoxy-5-bromo-6β,19-epoxy-5α-pregnan-20-one-20-ethyleneketal-18,11β-lactone (6b)

A suspension of 20 g of lead tetraacetate (washed with acetic acid,pressed and weighed moist) and 10 g of CaCO₃ in 600 ml of cyclohexanewas refluxed with stirring for 30 min. Five and three tenths g of I₂ wasadded, followed by the crude bromohydrin 5 (prepared the same day from3.0 g of 4b) dissolved in 25 ml of MDC. The mixture was refluxed withstirring and illumination with a 150 W spotlight bulb until the purplecolor disappeared: in 8 runs the time varied from 18 to 30 min withoutaffecting the yield. The mixture was cooled briefly in ice, while hotfiltered with suction, the precipitate was washed with a total of 100 mlof MDC and the combined filtrates were shaken for a few seconds with 400ml of 2.5% aqueous sodium thiosulfate. The aq. layer was quicklyseparated before a voluminous lead salt started to precipitate, and theorganic phase was washed with additional 200 ml of thiosulfate solution.The combined aqueous solutions were back-washed with 50 ml of MDC, andthe combined organic phases were washed with 100 ml of saturated aq.NaHCO₃, dried with Na₂ SO₄ and distilled in vacuo to a volume of about100 ml. Precipitation was completed by addition of 70 ml of PE andice-cooling. The crude 6b was collected and washed with PE, 3.6-3.9 g (asmall additional amount could be obtained by chromatography of thefiltrate). For purification, 13.5 g of the solid, absorbed on 60 g ofsilica gel, was chromatographed on a column of 700 g of silica gel.Elution with PE-acetone 4:1 containing a trace of Et₃ N gave infractions 32-44 (250 ml each) a total of 6.5 g of pure 6b, m.p. 142°-5°C. Rechromatography of the borderline fractions furnished additional 0.7g; λ^(KBr) _(max) 5.63, 5.72 and B 5.76μ; δ 2.039, 2.080 (s,s, 3-OAc,21-OAc), 2.89 (dd, J=11;6, 12-H), 3.97 (m, 21-H), 4.087 (d, J=11.7,21-H'), 3.97 (m, 20-dioxolane), 3.99, 4.04 (d,d, J=9;9, 19-H₂), 4.08(brs, 6α-H) and 5.18 (m, 3α-H) ppm.

5-Bromo-6β,19-epoxy-3β,21-dihydroxy-5α-pregnan-20-one-20-ethyleneketal-18,11β-lactone (6a)

A solution of 4.0 g of the diacetate 6b in 120 ml of hot methanol wastreated with a solution of 3.2 g of KHCO₃ in 40 ml of water, refluxedfor 1 h and concentrated in vacuo at 35° C. to a low volume. Water (100ml) and acetic acid (4 ml) were added and the mixture was extracted witha total of 350 ml of MDC. The combined extracts were washed with aq.NaHCO₃, dried with Na₂ SO₄, filtered and divided into two halves, eachof which was distilled in vacuo at 40° C. until the diol 6a was obtainedas a foam free of methanol.

6β,19-Epoxy-21-hydroxy-4-pregnene-3,20-dione-20-ethyleneketal-18,11β-lactone (8a)

Each portion of 6a (vide supra) was dissolved in 300 ml of hot acetonein a 1 L round bottom flask, cooled in an ice-bath with swirling for 5min and treated with 3 ml of the Jones reagent. After swirling in icefor additional 5 min 3 ml of isopropanol was added, followed by 5 g ofNaHCO₃ and 80 ml of water. The mixture was distilled in vacuo to removemost of the acetone until a volume of about 70 ml was reached, and thencooled in ice while the second half of 6a was processed in a similarmanner. Both batches were combined and filtered through a large sinteredglass funnel. The sucked-dry green precipiate was washed with a total of150 ml of MDC, the aqueous phase was extracted with a total of 200 ml ofMDC, the combined extracts were dried with Na₂ SO₄ and evaporated invacuo. The residual gum (2.7-2.9 g) containing 5-bromo-6β,19-epoxy-21-hydroxy-5α-pregnane-3,20-dione-20-ethylene ketal-18,11β-lactone (7)was refluxed in 100 ml of ethanol containing 5 g of sodium acetate for 1h, the solvent was evaporated to dryness at 40° C. and the residueworked up with water and MDC. The dried extracts were evaporated tofurnish 2.3-2.7 g of a crude gum which was chromatographed on 270 g ofsilica gel using CHCl₃ -ethanol 98:2 containing a trace of Et₃ N.Concentration of the early fractions yielded the desired ketal 8a whichwas collected with the aid of PE and washed with EtOAc: 1.23 g, m.p.188°-190° C.; λ^(KBr) _(max) 2.96, 5.60 and 5.99μ; δ 2.987 (dd,J=11.5;6.2, 12-H), 3.995 (m, 20-dioxolane), 3.499 (ABq, J=11.4, 21-H₂),3.50, 4.485 (d,d, J=8.4, 19-H₂), 4.715 (d, J=4.7, 6α-H), 4.776 (d, J=6.1, 11α-H) and 5.868 (s, 4-H) ppm. On acetylation the AB system appearsat 3.97 and B 4.10 (d,d, J=11;11, 21-H₂) ppm; EI: m/z 372 (M⁺ --CO₂ ;5%), 341 (M⁺ --CO₂ --CH₂ OH; 18), ##STR5##

Continued elution furnished 220 mg of6β,19-epoxy-21-hydroxy-4-pregnene-3,20-dione-18,11β-lactone (8b) which,after crystallization from acetone, had m.p. 229°-231° C. (dec.);λ^(KBr) _(max) 2.90, 5.66, 5.85 and 5.97μ; δ 3.16 (dd, J=11;6, 12-H₂),3.52, 4.47 (ABq, J=8.2, 19-H₂), 4.235 (d, J=18.4, 21-H), 4.48 (d,J=18.2, 21-H'), 4.730 (d, J=4, 6α-H), 4.907 (d, J=6.2, 11α-H) and 5.883(s, 4-H) ppm.

The 20-one 8b (42 mg) could also be obtained by hydrolysis of 8a (80 mg)in dioxane (3 ml) containing 5% HCl (0.5 ml) at room temperature for 48h, followed by the usual workup.

19,21-Dihydroxy-4-pregnen-3,20-dione-20-ethylene ketal-18,11β-lactone(9a)

A solution of 300 mg of the oxidolactone 8a in 20 ml of acetic acid wasdiluted with 2 ml of water and, with mechanical stirring, treated on thesteam bath over a 6 min period with 7 g of zinc powder. The mixture wascooled in ice to room temperature, filtered with suction, the zincwashed with 3×5 ml portions of acetic acid, the combined filtrates weredistilled in vacuo at 38° C. and the residual semisolid was worked upwith water and MDC. The combined MDC extracts were washed with aq.NaHCO₃, dried, evaporated in vacuo and the residue was crystallized fromacetone to furnish 72 mg of 9a, m.p. 225°-7° C.; λ^(KBr) _(max) 2.90,5.69 and 6.06μ; δ 3.46 (dd, J=12.0;7.7, 21-H), 3.52 (dd, J=12.0;5.3,21-H'), 3.99 (m, 20-dioxolane), 3.63 (dd, J=12.7;9.5, 19-H), 4.08 (dd,J=12.7;6.3, 19 -H'), 4.93 (d, J=6.1, 11α-H) and 5.87 (s, 4-H) ppm; EI:m/z 388 (M⁺ --CHOH; 80%), 370 (M⁺ --CHOH--H₂ O; 7), 358 (M⁺ --2CHOH;100) and 314 (M⁺ --2CHOH--CO₂ ; 6); CI: 419 (M⁺ +1; 31%), 401 (M⁺ +1--H₂O; 11) and 389 (M⁺ +1--CHOH; 100).

19,21-Dihydroxy-5-pregnene-3,20-dione-3,20-di-(ethyleneketal)-18,11β-lactone (10) A. Reduction of 8a with zinc-aceticacid-isopropanol.

A solution of 2.35 g of 8a in 350 ml of isopropanol and 30 ml of aceticacid was refluxed with stirring for 40 min with 60 g of zinc powder(activated by washing with 5% HCl, isopropanol and air-dried). Themixture was cooled, filtered with suction and the solid washed well withisopropanol. The combined filtrates were distilled to dryness in vacuo,the residue treated with 200 ml of water and extracted with 4×100 mlportions of MDC. The extracts were washed with aq. NaHCO₃, dried andevaporated to a gum (2.36 g) containing a mixture of19,21-dihydroxy-4-pregnene-3,20-dione-20-ethylene ketal-18,11β-lactone(9a) and its 5-ene isomer 9b in variable proportions.

B. Ketalization with ethylene glycol. A mixture of 9a and 9b (2.86 g)obtained as above was treated with 200 ml of ethylene glycol and 280 mgof p-toluenesulfonic acid, and distilled in vacuo with mechanicalstirring at 60°-5° C. over a 3.5 h period until a volume of about 50 mremained. The mixture was cooled, treated with 100 ml of saturated aq.NaHCO₃ and 20 ml of saturated NaCl solution, and extracted with 100 mland 3×70 ml portions of MDC. The dried extracts were evaporated in vacuoand the residual semisolid was chromatographed on 250 g of silica gelusing CHCl₃ -ethanol 98:2 with a trace of Et₃ N as the eluting agent toafford 950 mg of the diketal 10, m.p. 211°-3° C., resolidifying andmelting at 228° C. (EtOAc); λ^(KBr) _(max) 2.82 and 5.68μ; δ 2.977 (dd,J= 11.5;6.6, 12-H), 3.47 (dd, J=12.0;8, 21-H), 3.50 (dd, J=11.5;6,21-H'), 3.630 (dd, H=13;9, 19-H), 3.758 (dd, J=13;5.8, 19-H'), 3.976 (m,3 and 20-dioxolanes), 4.971 (d, J=6.2, 11α-H) and 5.51 (brdd, J˜5;1.5,6-H) ppm; EI: m/z 462 (M⁺,1%), 432 (M⁺ --CHOH; 73), 402 (M⁺ --2CHOH;100), ##STR6##

Purification of small amounts by TLC could be simplified by addingReichstein's Compound S and cortisol as fluorescing markers running,respectively, in front and behind 10 in CHCl₃ -ethanol 30:2.

11β,18-Epoxy-18,19,21-trihydroxy-5-pregnene-3,20-dione-3,20-di-(ethyleneketal)

A mechanically stirred solution of 742 mg of 10 in 20 ml of dry MDC wastreated in a N₂ atmosphere at -30° C. with 15 ml of 1M DIBAH solution intoluene from a syringe through a rubber septum. The mixture was slowlystirred at -20° C. for 1 hour, cooled to -30° C., treated again with 15ml of DIBAH solution, stirred at -20° C. for another hour, treated at-40° C. with 50 ml of MDC, then with 20 ml of 2M isopropanol solution intoluene, and at 0° C. with 1.5 ml of water. Next 10 g of celite and 15 gof Na₂ SO₄ were added, and after stirring for 15 min the mixture wasfiltered with suction through a large sintered glass funnel. Thegelatinous precipitate was washed with 100 ml of MDC, transferred into acolumn (30 mm diameter) and eluted with a total of 4 L of THF, applyingsuction to maintain a desirable dripping rate. The filtrate and eluatewere evaporated in vacuo and the oily residue chromatographed on 65 g ofsilica gel with CHCl₃ -ethanol 98:2 containing a trace of Et₃ N. Thesuitable fractions were pooled, the solvent was evaporated in vacuo andcrystallization of 11 initiated by addition of 7 ml of EtOAc. Theproduct was washed with more EtOAc, weighed 295 mg and had the m.p.196°-9.5° C.; λ^(KBr) _(max) 2.94μ; δ 3.5-3.7 (m, 21-H₂), 3.7-3.9 (m,19-H₂), 4.0 (m, 3 and 20-dioxolanes), 4.461 (d, J=6.2, 11α-H), 4.753 (d,J=6.6, 11α-H, minor isomer), 4.597 (s, 18-H, minor isomer), 5.168 (s,18-H), 5.49 (brd, J=3, 6-H) and 5.53 (brd, 6-H, minor isomer) ppm; EI:m/z 446 (M⁺ --H₂ O; 3%), 417 (M⁺ --H₂ O--CHO; 97), 399 (M⁺ --2H₂ O--CHO;100) and 390 (M⁺ --CH₂ OH--CO₂ ; 18).

19-Hydroxyaldosterone 12a 12b

A solution of 51 mg of diketal 11 in 4 ml of dioxane was treated with0.2 ml of 5% HCl and stored at 19° C. for 10 h, at which time TLCindicated the presence of mere traces of the starting material.Saturated aq. NaHCO₃ solution (10 ml) and MDC (50 ml) were added and theaqueous phase was reextracted with 4×15 ml portions of MDC. The dried(Na₂ SO₄) extracts were evaporated in vaco at 35° C., the residue wasapplied to 8 TLC plates 0.2 mm thick and developed with CHCl₃ -ethanol30:2.5. The appropriate zone was eluted with 10 ml of methanol each andthe combined solutions were evaporated in vacuo. The gum was dissolvedin a little MDC, the solution was filtered through a cotton plug toremove residual silica, evaporated in a stream of N₂ and scratched withether to afford 19 mg of crystalline 12, pure in TLC. The compound ismoderately soluble in warm ether and very soluble in water: by washingthe glassware and the cotton plug with water and evaporating in adesiccator over H₂ SO₄ additional 2 mg of pure 12 was obtained. Thecompound melts at 110°-120° C.; λ^(KBr) _(max) 2.93, 5.82 (w) and 6.02μ(FIG. 3); δ 4.065 (brd), 3.99 (brd, J=13, 21-H₂), 4.40, 4.245 (d,d,J=18;18, 21-H₂ ; this system only partially seen), 4.757 (d, J=6.3,19-H₂, one isomer), 4.969 (d, J=5.6, 19-H₂, another isomer), 5.115 (s,18-H, one isomer), 5.489 (s, 18-H, another isomer) and 5.827 (s, 4-H)ppm.

The key intermediate employed in the synthesis was the ketal 2 which wasprepared according to Lederman et al: Anal. Biochem. 51 (1973) 193 (FIG.1). It was obvious that the 18,11β lactone should be preserved as arelatively insensitive moiety up to the penultimate step of synthesis,that is the reduction to the hemiacetal 11.

The 5,6-double bond was then introduced, preferably by enolacetylationof 2, followed by sodium borohydride reduction.

However, attempts at conversion of 2 into 3 were met with failure due tothe sensitivity of the side-chain: acetic anhydride or isopropenylacetate with a variety of acidic catalysts led mostly to splitting offof the 20-ketal group; also acetyl chloride or acetic anhydride in warmpyridine caused extensive decomposition. On the other hand, the mildenol acetylation method employing acetic anhydride,trimethylchlorosilane and NaI at room temperature proved to be eminentlysuitable for the preparation of 3, which was best not purified butdirectly treated with sodium borohydride to afford the ketal 4a in 86%overall yield from 2.

The 3β-ol 4a was then acetylated and the diacetate 4b reacted withN-bromoacetamide and perchloric acid to furnish the bromohydrin 5, theketal group at C₂₀ being stabilized by the presence of the acetate atC₂₁.

The bromohydrin easily lost HBr during the isolation; the crude 5 was,therefore, directly reacted with lead tetraacetate, iodine and CaCO₃under illumination; chromatographic purification gave the cyclicderivative 6b in 60% overall yield from 4b.

The diacetate 6b was next saponified with boiling bicarbonate and thediol 6a selectively oxidized with the Jones reagent at C₃, the secondaryhydroxyl having preference over the primary C₂₁ -hydroxyl, withoutextensive hydrolysis of the ketal at C₂₀. The resulting bromoketone 7was unstable and therefore directly dehydrobrominated with sodiumacetate in ethanol: chromatography afforded the unsaturated ketone 8a in43% overall yield from 6b, and a small amount of the 20-one 8b.

Reductive ring opening of 6,19-oxides is commonly performed with zincand acetic acid, when partial acetylation of the 19-hydroxyl may takeplace. Since acetylation can be prevented by the use of aqueous aceticacid the ketal 8a was subjected to a brief treatment with zinc and 90%acetic acid, when a 23% of the desired 4-en-19-ol 9a was obtained. Zincor amalgamated zinc in refluxing isopropanol were ineffective; howeverzinc in a mixture of isopropanol and acetic acid, proved to be useful inthe present synthesis, allowing conversion of 8a into a mixture of 9aand its 5-ene isomer 9b, which was directly ketalized with ethyleneglycol and p-toluenesulfonic acid to yield the diketal 10 in 30% overallyield from 8a.

Reduction of the lactone function in 10 to the hemiacetal 11 with DIBAHwas next carried out. A large excess of the reagent was required and theproduct was accompanied by more polar by-products. Furthermore, theproducts of decomposition of DIBAH with isopropanol and water weretightly bound to the triol 11 which could be desorbed, preferably with alarge volume of THF. The product was purified by chromatography andproved to be a mixture of the two C₁₈ epimers, as indicated in the NMRspectrum by two sets of protons at positions 6, 11α and 18.

The synthesis of 19-hydroxyaldosterone (12) was then completed by a mildhydrolysis of its diketal 11. The hydroxyl at position 19 promotes thehydrolysis of the ketal at C₃, the rate being faster than of the diketalof aldosterone.

19-Hydroxyaldosterone is a crystalline solid, m.p. 110°-120° C., solublein most organic solvents and freely in water, from which it can berecovered unchanged by evaporation in a desiccator over sulfuric acid.It adheres tenaciously to residual silica from TLC, from which it can bereadily desorbed with water. Its i.r. spectrum in KBr exhibits a weaksaturated carbonyl, showing that in the solid state the molecule existsmostly in the cyclic 18,20-epoxy from 12b, ¹ H-NMR spectra indicate thatin CDCl₃ 19-hydroxyaldosterone exists mainly in two isomeric forms inthe ratio 7:5, as judged by the 18-H singlets; in D₂ O in the ratio is5:1.

We claim:
 1. 19-Hydroxyaldosterone of the formula ##STR7## 2.19-Hydroxyaldosterone.
 3. A pharmaceutical composition containing as anactive ingredient 19-hydroxyaldosterone in a pharmaceutically inertcarrier.
 4. A method for treating Addison's disease comprisingadministering the pharmaceutical composition of claim 3 to a patient. 5.A process for the production of 19-hydroxyaldosterone, whichcomprises:(a) acetylating 21-acetoxy-4-pregnene-3,20-dione-20-ethyleneketal-18,11β-lactone with acetic anhydride, trimethylchlorosilane andsodium iodide to produce3,21-diacetoxy-3,5-pregnadien-20-one-20-ethylene ketal-18,11β-lactone;(b) reducing the last mentioned compound with sodium borohydride toproduce the 3β-ol 3β,21-dihydroxy-5-pregnen-20-one-20-ethyleneketal-18,11β-lactone; (c) acetylating the 3β-ol with acetic anhydrideand pyridine to produce the diacetate 3β,21-diacetoxy-5-αpregnan-20-one-20-ethylene ketal-18,11β lactone; (d) reacting thediacetate with N-bromoacetamide and perchloric acid to produce thebromohydrin 3β,21-diacetoxy-5-bromo-6β-hydroxy-5α-pregnane-20-one-20-ethylene ketallactone; (e) reacting the bromohydrin with lead tetraacetate; iodine andcalcium carbonate to produce the diacetate3β,21-diacetoxy-5-bromo-6β,19-epoxy-5α-pregnan-20-one-20-ethyleneketal-18,11β-lactone; (f) saponifying the last mentioned diacetate withboiling bicarbonate to produce the diol5-bromo-6β,19-epoxy-3β,21-hydroxy-5α-pregnan-20-one-20-ethyleneketal-18,11β-lactone; (g) selectively oxidizing the diol with Jonesreagent to produce the bromoketone5-bromo-6β,19-epoxy-21-hydroxy-5-pregnane-3,20-dione-20-ethyleneketal-18,11β-lactone; P1 (h) dehydrobrominating the bromoketone withsodium acetate to produce the unsaturated ketone6β,19-epoxy-21-hydroxy-4-pregnene-3,20-dione-20-ethyleneketal-18,11β-lactone; (i) subjecting the unsaturated ketone to reductivering opening with zinc in acetic acid and isopropanol to produce19,21-dihydroxy-4-pregnen-3,20-dione-20-ethylene ketal-18, 11β-lactoneand its 5-ene isomer; (j) ketalizing the mixture with ethylene glycoland p-toluenesulfonic acid to produce the diketal19,21-dihydroxy-5-pregnene-3,20-dione-3,20-di-(ethyleneketal)-18,11β-lactone; (k) reducing the diketal with diisobutyl aluminumhydride to the hemiacetal 11β,18 -epoxy-18,19,21-trihydroxy-5-pregnene3,20-di-(ethylene ketal); and (l) hydrolyzing the hemiacetal with acidto produce 19-hydroxyaldosterone.